Congenital disorder of deglycosylation

Summary

Congenital disorder of deglycosylation (MONDO:0031376) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 797

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital disorder of deglycosylation
Mondo ID	MONDO:0031376
OMIM	615273
DOID	DOID:0060991
UMLS	C3808991
MedGen	815321
GARD	0025697
Is cancer (heuristic)	no

Data availability: 797 ClinVar variants · 48 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of deglycosylation

Related subtypes (92): thiopurine metabolic disease, hypercalcemia, infantile, hypermanganesemia with dystonia, abdominal obesity-metabolic syndrome, plasma protein metabolism disease, inherited lipid metabolism disorder, lysosomal storage disease, striatonigral degeneration, inborn metal metabolism disorder, inborn vitamin metabolic disorder, chondrocalcinosis 2, Ehlers-Danlos syndrome, spondylodysplastic type, fish eye disease, aromatase excess syndrome, spondyloepiphyseal dysplasia with congenital joint dislocations, hypertriglyceridemia 1, autosomal dominant myoglobinuria, diastrophic dysplasia, hemolytic anemia due to diphosphoglycerate mutase deficiency, multiple epiphyseal dysplasia type 4, atelosteogenesis type II, inherited threoninemia, inborn glycerol kinase deficiency, achondrogenesis type IB, diabetes mellitus, noninsulin-dependent, 1, diabetes mellitus, noninsulin-dependent, 2, renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, diabetes mellitus, noninsulin-dependent, 3, hypercholesterolemia, familial, 4, hypoalphalipoproteinemia, primary, 1, autosomal recessive proximal renal tubular acidosis, diabetes mellitus, noninsulin-dependent, 4, normophosphatemic familial tumoral calcinosis, apolipoprotein c-III deficiency, hypotonia-failure to thrive-microcephaly syndrome, chondrodysplasia with joint dislocations, gPAPP type, gluthathione peroxidase deficiency, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diabetes mellitus, noninsulin-dependent, 5, congenital disorder of glycosylation, monogenic diabetes, 2-hydroxyglutaric aciduria, familial hypoparathyroidism, familial intrahepatic cholestasis, inborn aminoacylase deficiency, disorder of lysosomal-related organelles, inborn disorder of porphyrin metabolism, disorder of metabolite absorption and transport, autosomal dominant proximal renal tubular acidosis, neurodegeneration with brain iron accumulation, ferro-cerebro-cutaneous syndrome, familial hypocalciuric hypercalcemia, hypophosphatasia, hereditary amyloidosis, peroxisomal disease, inborn disorder of amino acid and other organic acid metabolism, inborn carbohydrate metabolic disorder, inborn disorder of energy metabolism, inborn disorder of biogenic amine metabolism and transport, inborn disorder of purine or pyrimidine metabolism, spondyloepimetaphyseal dysplasia, PAPSS2 type, hereditary lipodystrophy, hereditary recurrent myoglobinuria, DNA repair disease, 4-hydroxyphenylacetic aciduria, 5-nucleotidase syndrome, antigen-peptide-transporter 2 deficiency, APO A-i deficiency, cardiomyopathy hypogonadism metabolic anomalies, deficiency of coenzyme q cytochrome c reductase, defective apolipoprotein b-100, sulfide quinone oxidoreductase deficiency, hypoalphalipoproteinemia, primary, 2, uridine-cytidineuria, NAD(P)HX dehydratase deficiency, inborn disorder of aspartate family metabolism, weinstein kliman scully syndrome, glycoprotein metabolism disease, inherited thyroid metabolism disease, tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 3, combined ApoA-I and ApoC-III deficiency, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, tumoral calcinosis, hyperphosphatemic, familial, 1, Waldenstrom macroglobulinemia, mucopolysaccharidosis or mucopolysaccharidosis-like disorder, disorder of peptide and amine metabolism, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis, Lane Hamilton syndrome, SQSTM1-related multisystem proteinopathy, hypertriglyceridemia 2, autosomal dominant dopa-responsive dystonia

Subtypes (2): congenital disorder of deglycosylation 2, congenital disorder of deglycosylation 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

312 likely benign, 171 uncertain significance, 65 pathogenic, 17 benign, 15 conflicting classifications of pathogenicity, 9 likely pathogenic, 7 pathogenic/likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069924	NM_018297.4(NGLY1):c.1449del (p.Cys484fs)	NGLY1	Pathogenic	criteria provided, single submitter
1070987	NM_018297.4(NGLY1):c.1771C>T (p.Gln591Ter)	NGLY1	Pathogenic	criteria provided, single submitter
1070999	NM_018297.4(NGLY1):c.999C>A (p.Tyr333Ter)	NGLY1	Pathogenic	criteria provided, single submitter
1071020	NC_000003.11:g.(?25760931)(25831376_?)del	NGLY1	Pathogenic	criteria provided, single submitter
1072311	NM_018297.4(NGLY1):c.177del (p.Ala60fs)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073150	NM_018297.4(NGLY1):c.1748G>A (p.Trp583Ter)	NGLY1	Pathogenic	criteria provided, single submitter
1076851	NM_018297.4(NGLY1):c.1515del (p.Arg506fs)	NGLY1	Pathogenic	criteria provided, single submitter
1184978	NM_018297.4(NGLY1):c.571C>T (p.Gln191Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
126422	NM_018297.4(NGLY1):c.1370dup (p.Arg458fs)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
126423	NM_018297.4(NGLY1):c.1202GAA[1] (p.Arg402del)	NGLY1	Pathogenic	no assertion criteria provided
126424	NM_018297.4(NGLY1):c.1624C>T (p.Arg542Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324809	NM_018297.4(NGLY1):c.1764_1785del (p.Asp588fs)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1375055	NM_018297.4(NGLY1):c.1551G>A (p.Trp517Ter)	NGLY1	Pathogenic	criteria provided, single submitter
1392868	NM_018297.4(NGLY1):c.997dup (p.Tyr333fs)	NGLY1	Pathogenic	criteria provided, single submitter
1396095	NM_018297.4(NGLY1):c.-18GCCCGCTGGCGCTCAAGCATGGCGGCGGCGGC[3] (p.Leu6fs)	NGLY1	Pathogenic	criteria provided, single submitter
1415810	NM_018297.4(NGLY1):c.1431_1435del (p.Lys477fs)	NGLY1	Pathogenic	criteria provided, single submitter
1431487	NM_018297.4(NGLY1):c.948_949insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGGGCCAATTGTTTT (p.Thr317delinsPhePhePhePhePhePheXaaXaaXaaXaaAspLeuValIleArgProProArgProProLysValLeuGlyLeuGlnAlaTer)	NGLY1	Pathogenic	criteria provided, single submitter
1451269	NM_018297.4(NGLY1):c.1722_1723insCA (p.Thr575fs)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454942	NM_018297.4(NGLY1):c.1474C>T (p.Gln492Ter)	NGLY1	Pathogenic	criteria provided, single submitter
1456986	NM_018297.4(NGLY1):c.1168C>T (p.Arg390Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458545	NM_018297.4(NGLY1):c.904_905del (p.Leu302fs)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
1955467	NM_018297.4(NGLY1):c.14_15insGCCCGCTGGCGCTCAAGCATGGCGGCGGCGGCGGC (p.Leu6fs)	NGLY1	Pathogenic	criteria provided, single submitter
2015044	NM_018297.4(NGLY1):c.1882del (p.Gln628fs)	NGLY1	Pathogenic	criteria provided, single submitter
2067984	NM_018297.4(NGLY1):c.1736del (p.Gly579fs)	NGLY1	Pathogenic	criteria provided, single submitter
2132011	NM_018297.4(NGLY1):c.236del (p.Gly79fs)	NGLY1	Pathogenic	criteria provided, single submitter
221576	NM_018297.4(NGLY1):c.931G>A (p.Glu311Lys)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
221577	NM_018297.4(NGLY1):c.1604G>A (p.Trp535Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
221578	NM_018297.4(NGLY1):c.622C>T (p.Gln208Ter)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
221579	NM_018297.4(NGLY1):c.347C>G (p.Ser116Ter)	NGLY1	Pathogenic	no assertion criteria provided
221581	NM_018297.4(NGLY1):c.730T>C (p.Trp244Arg)	NGLY1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NGLY1	Orphanet:404454	Alacrimia-choreoathetosis-liver dysfunction syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NGLY1	HGNC:17646	ENSG00000151092	Q96IV0	Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NGLY1	Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase	Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NGLY1	Enzyme (other)	yes	3.5.1.52	Transglutaminase-like, Peptide_N_glycanase_PAW_dom, Galactose-bd-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ cell	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NGLY1	290	ubiquitous	marker	sperm, male germ cell, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NGLY1	1,442

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NGLY1	Q96IV0	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	423.0×	0.002	NGLY1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycoprotein catabolic process	1	1053.2×	0.003	NGLY1
positive regulation of BMP signaling pathway	1	455.5×	0.003	NGLY1
protein folding	1	103.4×	0.010	NGLY1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NGLY1	DACTINOMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NGLY1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DACTINOMYCIN	4	NGLY1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NGLY1	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NGLY1	3.5.1.52	peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DACTINOMYCIN	4	NGLY1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NGLY1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.